It is apparent that successful cancer chemotherapy often involves a combination of antitumor agents at precise dosage schedules. Both in animals and man, empirical combination regimens have led to improvement in therapy. The synergism observed with certain drug combinations must have a pharmacological and biochemical basis. Knowledge of the underlying pharmacological and biochemical components which produce synergism would make the choice of combinations as well as their optimal scheduling a more predictable and rational process. We wish to determine the biochemical and pharmacological basis for the synergism observed in a rodent tumor system using drug pairs involving 4 drugs, adriamycin, cyclophosphamide, 5-fluorouracil, and methotrexate, all of which are useful in treating human solid tumors. This work will be carried out with mice bearing L1210 ascites cells and the L1210 cells in culture. In our view the application of studies during combination chemotherapy on pharmacokinetics, mechanism of drug action, duration, and recovery from drug action, cell cycle kinetics, and DNA repair mechanisms, should enable us to begin to understand the basis for drug synergism. The need for this information, which should lead to predictable and selective antitumor activity during combination chemotherapy of solid tumors, is enormous.